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Mutations of thyrotropin receptor gene
A Porcellini1, G Fenzi, E V Avvedimento
1Dipartimento di Biologia, e Patologia Molecolare e Cellulare L. Califano, Facoltà di Medicina, Università Federico II, Naples, Italy.
Abstract:
Thyrotropin is the primary pituitary hormone which stimulates the growth and differentiation of thyroid cells. TSH binds a specific receptor present in the plasma membrane of thyroid cells and signals the G protein transducers, which activate different effectors, mainly adenyl cyclase and phospholipase C. The TSH receptor belongs to a broad class of receptors known as seven-loop receptors because they contain a long stretch of amino acids which cross the plasma membrane seven times. Mutations in the TSH receptor gene have been found in hyperfunctioning thyroid adenomas. These mutations are: (a) somatic (present only in the tumor), (b) dominant (only one copy of the gene is affected), and (c) lead to the constitutive activation of the cAMP signaling cascade. Most mutations which have been identified occur in the intracellular loop III and in the transmembrane domain VI. Germline mutations in the same regions of the receptor have been found in congenital nonautoimmune hyperthyroidism. In addition, germ line mutations have been described in the extracellular domain of the receptor leading to increased TSH levels. The clinical implications of these findings are discussed.
Insights
Mutations in the TSH receptor gene can cause hyperfunctioning thyroid adenomas and congenital hyperthyroidism by constitutively activating signaling pathways. These genetic changes highlight the TSH receptor's critical role in thyroid function.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Thyrotropin (TSH) is a crucial pituitary hormone regulating thyroid cell growth and differentiation.
- TSH exerts its effects by binding to the TSH receptor, a G protein-coupled receptor, activating signaling cascades like adenyl cyclase and phospholipase C.
- The TSH receptor, a seven-transmembrane domain receptor, is implicated in thyroid disorders when mutations occur.
Purpose of the Study:
- To investigate the role of TSH receptor gene mutations in thyroid hyperfunction.
- To identify the specific regions and types of mutations associated with hyperfunctioning thyroid adenomas and congenital hyperthyroidism.
- To discuss the clinical significance of these TSH receptor mutations.
Main Methods:
- Analysis of TSH receptor gene mutations in patients with hyperfunctioning thyroid adenomas.
- Identification of somatic and germline mutations in different domains of the TSH receptor.
- Correlation of mutation types with constitutive activation of cAMP signaling pathways.
Main Results:
- Somatic, dominant mutations in the TSH receptor gene, particularly in intracellular loop III and transmembrane domain VI, lead to constitutive cAMP signaling and hyperfunctioning thyroid adenomas.
- Germline mutations in similar regions of the TSH receptor are associated with congenital nonautoimmune hyperthyroidism.
- Germline mutations in the extracellular domain of the TSH receptor can result in elevated TSH levels.
Conclusions:
- TSH receptor gene mutations are a significant cause of thyroid hyperfunction, including adenomas and congenital hyperthyroidism.
- The location and type of mutation dictate the clinical presentation and hormonal imbalance.
- Understanding these mutations is vital for diagnosing and managing thyroid disorders.